Xuan Liu
Professor of Biochemistry
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Molecular Biology
Signal Transduction Ph.D., West Virginia University 1990 VOICE: 951-827-4350 |
Introduction
Alteration or loss of the p53 tumor suppressor gene is the most frequent lesion detected in cancer. In normal cells, the p53 protein plays a critical role in the regulation of cell proliferation, serving as a checkpoint function to monitor DNA damage and to arrest cell division prior to replication. The biochemical activity of p53 that is required for this relies on its ability to bind to specific DNA sequences and to function as a transcription factor. Our laboratory is interested in understanding the molecular mechanisms by which p53 functions as a transcription factor and by which cells regulate p53 transcriptional activity. In this regard, our research has focused on the following 3 areas: 1) understanding molecular interplay between p53 and a cell cycle protein TAF1; 2) characterizing regulation of p53 by B56gamma-specific PP2A; and 3) defining crosstalk between p53 and the PTEN tumor suppressor pathways.
Project 1: Molecular interplay between p53 and TAF1
TAF1 is the largest subunit of transcription factor TFIID and is also a cell cycle regulatory protein important for progression through the G1 phase and apoptosis. TAF1 possesses an intrinsic protein kinase activity. We show that TAF1 phosphorylates p53 at Thr55. This phosphorylation and the resultant destabilization of p53 play a role in TAF1-induced G1 progression. Importantly, the Thr55 phosphorylation was reduced following DNA damage, suggesting that this phosphorylation plays a role in regulation of p53 in response to DNA damage (Li et al, 2004).
To understand the molecular mechanisms, we show that Thr55 phosphorylation increases the interaction of p53 with its nuclear export receptor, CRM1/Exportin1. As a consequence, the p53 protein is exported to the cytoplasm and subsequently degraded. Inhibition of TAF1 kinase disrupts p53-CRM1 interaction and restores p53 nuclear localization and function (Cai and Liu, manuscript submitted). These results support the notion that Thr55 phosphorylation plays a role in regulation of p53 function.
Interestingly, evidences from my laboratory also indicate that, upon DNA damage, acetylated p53 activate transcription by interacting with double bromodomains of TAF1 and recruits TAF1 to the p53 transcription target p21 promoter (Li et al, 2007). To understand this p53-TAF1 interplay, we also found that TAF1 is capable of phosphorylating p53 when recruited to the promoter (Piluso, unpublished data). These preliminary results suggest that Thr55 phosphorylation may also play an important role in turning-off of p53-mediated transcription.
Project 2: Dephosphorylation of p53 by PP2A activates p53
To gain insights into the regulation of Thr55 phosphorylation, we undertook a search and found protein phosphatases 2A (PP2A) that is responsible for the p53 dephosphorylation after DNA damage (Li et al, 2007). PP2A holo-enzyme, consisting of a catalytic subunit, a scaffolding subunit and a regulatory subunit (B), functions as a positive and negative regulator of the cell cycle, in the latter capacity potentially acting as a tumor suppressor. The potential tumor suppressive function of PP2A is likely achieved by a very small subset of PP2A holoenzymes with particular B subunit compositions. For example, a B56 subunit family member, B56gamma3, has been implicated in conferring tumor suppressive functions to the holoenzyme. Interestingly, we show that, upon DNA damage, a complex including B56gamma3-specific PP2A and p53 is formed, which leads to Thr55 dephosphorylation, induction of p53 transcription target p21, and inhibition of cell proliferation and transformation (Li et al, 2007; Shouse et al, 2008). These findings suggest a molecular mechanism for B56gamma3-mediated tumor suppression and, more importantly, provide a potential route for regulation of specific PP2A complex function.
Project 3: Cross-talking between p53 and the tumor suppressor PTEN
Tumor suppressor PTEN is frequently mutated in human cancer. We show that PTEN physically associates with endogenous p53 and stimulates the transcription activity of p53 by blocking its protein degradation and modulating its DNA binding. In collaboration with Hong Wu’s group at UCLA, we found that the onset and spectrum of tumor development in p53+/-;Pten+/- mice are similar to p53-/- animals. This study provided first evidence that PTEN directly modulates p53 function independent of its phosphatase activity (Freeman et al, 2003).
To fellow up these interesting observations, my laboratory further shows that PTEN forms a complex with p300 in the nucleus and plays a role in maintenance of high p53 acetylation in response to DNA damage. As a consequence, p300 is required for nuclear PTEN-regulated cell cycle arrest. Our results suggest a physiological role for the PTEN tumor suppressor in the nucleus and provide a molecular explanation for our previous observation that PTEN controls p53 protein levels independent of its phosphatase activity (Li et al, 2006).
Selected Publications:
Freeman, D.J., A.G. Li, G. Wei, H.-H. Li, R. Lesche, A.D. Whale, H. Martinez-Diaz, N. Rozengurt, X. Liu* and H. Wu*. (2003). PTEN tumor suppressor regulates p53 protein levels and activity through both phosphatase-dependent and -independent mechanisms. Cancer Cell 3:117-130 *corresponding authors
Li, H.-H., A.G. Li, H.M. Sheppard and X. Liu. (2004). Phosphorylation on Thr-55 by TAF1 mediates degradation of p53: a role for TAF1 in cell cycle regulation. Molecular Cell 13:867-878
Wei, G., A.G. Li and X. Liu. (2005). Insights into selective activation of p53 DNA binding by c-Abl. Journal of Biological Chemistry 280:12271-12278
Li, A.G., L.G. Piluso, X. Cai, G. Wei, W.R. Sellers and X. Liu. (2006). Mechanistic insights into maintenance of high p53 acetylation by PTEN. Molecular Cell 23:575-587
Li, H.-H., X. Cai, G.P. Shouse, L.G. Piluso and X. Liu. (2007). A specific PP2A regulatory subunit, B56gamma, mediates DNA damage-induced dephosphorylation of p53 at Thr55. EMBO Journal 26:402-411
Li, A.G., L.G. Piluso, X. Cai, B.J. Gadd, A.G. Ladurner and X. Liu. (2007). An acetylation switch in p53 mediates holo-TFIID recruitment. Molecular Cell 28:408-421
Shouse, G.P., X. Cai and X. Liu. (2008). Serine 15 phosphorylation of p53 directs its interaction with B56gamma and the tumor suppressor activity of B56gamma-specific PP2A, Molecular Cellular Biology, 28:448-456
Cai, X. and X. Liu. (2008) Inhibition of Thr55 phosphorylation restores p53 nuclear localization and sensitizes cancer cells to DNA damage. PNAS in press.
Liu Lab (2006)
Liu Lab (2008)
